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A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors
Sponsor study identifier
Secondary identifiers
OTHER · Loxo Oncology, Inc
OTHER · CTIS (EU)
EUDRACT_NUMBER
NIH
interventional
154
22 countries
45
Study Start
December 16, 2015
Actual (reported)Primary Completion
July 20, 2024
Actual (reported)Study Completion
September 30, 2026
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
The study is being done to test the safety of a cancer drug called larotrectinib in children. The cancer must have a change in a particular gene (NTRK1, NTRK2 or NTRK3). Larotrectinib blocks the actions of these NTRK genes in cancer cells and can therefore be used to treat cancer. The first study part (Phase 1) is done to determine what dose level of larotrectinib is safe for children, how the drug is absorbed and changed by their bodies and how well the cancer responds to the drug. The main purpose of the second study part (Phase 2) is to investigate how well and how long different cancer types respond to the treatment with larotrectininb.
Registry-reported information. Elapsed time and enrollment totals alone do not measure study progress or recruitment pace.
September 30, 2026
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
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Dates and qualifiers reported by the registry. Estimated dates do not confirm that a milestone has occurred.
December 10, 2015
Actual (reported)December 16, 2015
Actual (reported)December 22, 2015
Actual (reported)July 20, 2024
Actual (reported)September 30, 2026
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
Phase 1: Number of participants in an assigned dose cohort with treatment emergent adverse events (TEAEs) by grade assessed by NCI-CTCAE v 4.03 who experience a DLT
DLT: Dose-limiting toxicity. NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events.
From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)
Phase 1: Number of participants with TEAEs
From first dose of larotrectinib up to 93 months
Phase 1: Severity of TEAEs
From first dose of larotrectinib up to 93 months
Patients will receive the different levels of dose on Day 1 (BID in accordance with the cohort assignment). Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)
Patients who are enrolled in the expansion cohort, following the formal dose escalation phase of the study. Distinct from the Phase 1 dose escalation cohort, the Phase 1 expansion cohort will enroll pediatric patients with advanced solid or primary CNS tumors with a documented NTRK gene fusion, or in the case of IFS, CMN or SBC with documented ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by NGS. This expansion cohort will follow the same schedule of assessments as the dose escalation cohorts. (arm closed)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Children's Hospital Los Angeles - Hematology/Oncology
Los Angeles, California, 90027, United States
UCLA Jonsson Comprehensive Cancer Center
Los Angeles, California, 90095-1781, United States
Lucille Packard Children's Hospital Stanford - Pediatric Nephrology
Palo Alto, California, 94304, United States
Nemours Children's Hospital - Florida - Hematology / Oncology
Orlando, Florida, 32827, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Memorial Sloan Kettering Cancer Center New York - Main Campus
New York, New York, 10065, United States
Mascarenhas L, Ollis C, Singh Y, Menachery L, Burcoveanu DI, De La Cuesta E, van Tilburg CM, Laetsch TW. Cancer control after pausing treatment with larotrectinib in responding children with sarcoma and a TRK fusion: a plain language summary. Future Oncol. 2026 Aug 19:1-10. doi: 10.1080/14796694.2026.2711519. Online ahead of print.
Ajani JA, D'Amico TA, Bentrem DJ, Corvera CU, Das P, Enzinger PC, Enzler T, Gerdes H, Gibson MK, Grierson P, Gupta G, Hofstetter WL, Ilson DH, Jalal S, Kim S, Kleinberg LR, Klempner S, Lacy J, Lee B, Licciardi F, Lloyd S, Ly QP, Matsukuma K, McNamara M, Merkow RP, Miller AM, Mukherjee S, Mulcahy MF, Perry KA, Pimiento JM, Reddi DM, Reznik S, Roses RE, Strong VE, Su S, Uboha N, Wainberg ZA, Willett CG, Woo Y, Yoon HH, McMillian NR, Stein M. Gastric Cancer, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw. 2025 May;23(5):169-191. doi: 10.6004/jnccn.2025.0022.
154 participants (actual enrollment reported by the registry).
First Submitted
December 10, 2015
First Posted
December 22, 2015
Study Start
December 16, 2015
Actual (reported)Phase 2: Overall response rate (ORR) by IRRC
Proportion of participants with a best overall response of complete response (CR) or partial response (PR) as determined by an independent radiology review committee (IRRC) based on Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, Response Assessment in Neuro Oncology (RANO) or International Neuroblastoma Response Criteria (INRC) as appropriate to tumor type who express NTRK gene fusions.
From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months
Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
Cohort 1 and 2: Cycle 1 Day 1 (C1D1) at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dose
Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma
Cohort 1 and 2: C1D1 at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dose
Phase 1: Oral clearance (CL/F)
Cohort 1 and 2: C1D1 at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dos
Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib
C1D1 in conjunction with the post-dose 1-hour PK sample
Phase 1: Maximum tolerated dose (MTD)
From C1D1 to C1D28 of treatment of each participant in each of the assigned dose cohort, up to 16 months
Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)
Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)
Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation.
Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. Patients in this group will undergo bone health assessments in addition to all other efficacy and safety assessments.
Contact the study team to confirm eligibility.
Cincinnati Children's Hospital Medical Center | Division of Nephrology and Hypertension
Cincinnati, Ohio, 45229, United States
Children's Hospital of Philadelphia - Hematology/Oncology
Philadelphia, Pennsylvania, 19104, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105, United States
University of Texas Southwestern Medical Center
Dallas, Texas, 75390, United States
Seattle Children's Hosptial - Oncology
Seattle, Washington, 98105, United States
Sydney Children's Hospital
Sydney, New South Wales, 2031, Australia
Women's and Children's Hospital
North Adelaide, South Australia, 5006, Australia
Royal Children's Hospital Melbourne
Parkville, Victoria, 3052, Australia
BC Children's Hospital - Hematology/Oncology
Vancouver, British Columbia, V6H 3N1, Canada
The Hospital for Sick Children (SickKids)
Toronto, Ontario, M5G 1X8, Canada
CHU Sainte-Justine
Montreal, Quebec, H3T 1C5, Canada
Beijing Children's Hospital, Capital Medical University
Beijing, Beijing Municipality, 100045, China
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, 510000, China
Tianjin Medical University Cancer Institute & Hospital
Tianjin, 300000, China
FN Brno - Detska nemocnice
Brno, 613 00, Czechia
Fakultni nemocnice v Motole
Prague, 150 06, Czechia
Rigshospitalet - Børn og Unge
Copenhagen, 2100, Denmark
Institut Curie - Ulm - Paris
Paris, 75248, France
Gustave Roussy - Departement Oncologie-Radiotherapie
Villejuif, 94805, France
Universitaetsklinikum Heidelberg - KiTZ | Klinik für Paediatrische Onkologie, Haematologie, Immunologie und Pneumologie
Heidelberg, Baden-Wurttemberg, 69120, Germany
KLINIKUM STUTTGART - Olgahospital | Paediatrie 5 (Onkologie, Haematologie, Immunologie)
Stuttgart, Baden-Wurttemberg, 70174, Germany
Charité - Campus Virchow-Klinikum (CVK), Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie
Berlin, 13353, Germany
Children's Health Ireland Crumlin
Crumlin, Dublin, 12, Ireland
Clalit Health Services Schneider Children's Medical Center
Petah Tikva, 4920235, Israel
Fondazione IRCCS Istituto Nazionale dei Tumori - S. C. Pediatria Oncologica
Milan, Lombardy, 20133, Italy
Kanagawa Children's Medical Center
Yokohama, Kanagawa, 252-8555, Japan
National Cancer Center Hospital
Chuo-ku, Tokyo, 104-0045, Japan
Kyushu University Hospital
Fukuoka, 812-8582, Japan
Prinses Maxima Centrum
Utrecht, 3584 CS, Netherlands
Uniwersyteckie Centrum Kliniczne
Gdansk, 80-214, Poland
Severance Hospital, Yonsei University Health System
Seoul, Seoul Teugbyeolsi, 03722, South Korea
Seoul National University Hospital
Seoul, Seoul Teugbyeolsi, 3080, South Korea
Ciutat Sanitaria i Universitaria de la Vall d'Hebron
Barcelona, 08035, Spain
Karolinska Universitetssjukhuset i Solna
Stockholm, 171 76, Sweden
Universitätskinderspital Zürich
Zurich, 8032, Switzerland
Istanbul Universitesi Istanbul Tip Fakultesi
Istanbul, 34093, Turkey (Türkiye)
Governmental Noncommercial Institution "National Cancer Institute
Kyiv, 03022, Ukraine
Western Ukrainian Specialized Pediatric Medial Centre, Surgical Department
Lviv, 79035, Ukraine
Royal Marsden NHS Trust (Surrey)
Sutton, Surrey, SM2 5PT, United Kingdom
Brose MS, Westphalen CB, Pan X, Bernard-Gauthier V, Kurtinecz M, Guo H, Aris V, Brett NR, Majdi A, Subbiah V, Pennell NA, Kehl KL, Drilon A. Larotrectinib Compared With Real-World Non-Tropomyosin Receptor Kinase Inhibitor Therapies in Patients With Tropomyosin Receptor Kinase Fusion Cancer. JCO Precis Oncol. 2025 Apr;9:e2400500. doi: 10.1200/PO-24-00500. Epub 2025 Apr 23.
Mascarenhas L, DuBois SG, Albert CM, Bielack S, Orbach D, Federman N, Geoerger B, Nagasubramanian R, Zhang Y, Chisholm J, Gallego Melcon S, Goto H, Morgenstern DA, Owens C, Pappo AS, Perreault S, Schulte JH, Shukla N, Zwaan CM, Neu N, Bernard-Gauthier V, De La Cuesta E, van Tilburg CM, Laetsch TW. Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors. J Clin Oncol. 2025 Apr;43(10):1180-1187. doi: 10.1200/JCO.24.00848. Epub 2025 Jan 27.
Nahon-Esteve S, Orbach D, Le Loarer F, Hofman P, Lassalle S. Fibroblastic orbital tumour with NTRK1 fusion transcript: when TRK inhibitors rescue surgery. Can J Ophthalmol. 2024 Aug;59(4):e407-e409. doi: 10.1016/j.jcjo.2023.11.008. Epub 2023 Dec 11. No abstract available.
Subbiah V, Burris HA 3rd, Kurzrock R. Revolutionizing cancer drug development: Harnessing the potential of basket trials. Cancer. 2024 Jan;130(2):186-200. doi: 10.1002/cncr.35085. Epub 2023 Nov 7.
Kummar S, Shen L, Hong DS, McDermott R, Keedy VL, Casanova M, Demetri GD, Dowlati A, Melcon SG, Lassen UN, Leyvraz S, Liu T, Moreno V, Patel J, Patil T, Mallick AB, Sousa N, Tahara M, Ziegler DS, Norenberg R, Arvis P, Brega N, Drilon A, Tan DSW. Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas. Cancer. 2023 Dec 1;129(23):3772-3782. doi: 10.1002/cncr.35036. Epub 2023 Sep 28.
Bokemeyer C, Paracha N, Lassen U, Italiano A, Sullivan SD, Marian M, Brega N, Garcia-Foncillas J. Survival Outcomes of Patients With Tropomyosin Receptor Kinase Fusion-Positive Cancer Receiving Larotrectinib Versus Standard of Care: A Matching-Adjusted Indirect Comparison Using Real-World Data. JCO Precis Oncol. 2023 Jan;7:e2200436. doi: 10.1200/PO.22.00436.
Rudzinski ER, Drilon A, Moore A, Spinosa S, Willi M, Laetsch TW. Testing methods to diagnose TRK fusion cancer - a plain language summary and patient perspective. Future Oncol. 2022 Dec;18(38):4141-4151. doi: 10.2217/fon-2022-0863. Epub 2023 Jan 6.
Doz F, van Tilburg CM, Geoerger B, Hojgaard M, Ora I, Boni V, Capra M, Chisholm J, Chung HC, DuBois SG, Gallego-Melcon S, Gerber NU, Goto H, Grilley-Olson JE, Hansford JR, Hong DS, Italiano A, Kang HJ, Nysom K, Thorwarth A, Stefanowicz J, Tahara M, Ziegler DS, Gavrilovic IT, Norenberg R, Dima L, De La Cuesta E, Laetsch TW, Drilon A, Perreault S. Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro Oncol. 2022 Jun 1;24(6):997-1007. doi: 10.1093/neuonc/noab274.
Bebb DG, Banerji S, Blais N, Desmeules P, Gill S, Grin A, Feilotter H, Hansen AR, Hyrcza M, Krzyzanowska M, Melosky B, Noujaim J, Purgina B, Ruether D, Simmons CE, Soulieres D, Torlakovic EE, Tsao MS. Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults. Curr Oncol. 2021 Jan 15;28(1):523-548. doi: 10.3390/curroncol28010053.
Perreault S, Chami R, Deyell RJ, El Demellawy D, Ellezam B, Jabado N, Morgenstern DA, Narendran A, Sorensen PHB, Wasserman JD, Yip S. Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients. Curr Oncol. 2021 Jan 9;28(1):346-366. doi: 10.3390/curroncol28010038.
Bielack SS, Cox MC, Nathrath M, Apel K, Blattmann C, Holl T, Jenewein R, Klenk U, Klothaki P, Muller-Abt P, Ortega-Lawerenz S, Reynolds M, Scheer M, Simon-Klingenstein K, Stegmaier S, Tupper R, Vokuhl C, von Kalle T. Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion. Ann Oncol. 2019 Nov;30 Suppl 8:viii31-viii35. doi: 10.1093/annonc/mdz382. Epub 2019 Dec 24.
Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531-540. doi: 10.1016/S1470-2045(19)30856-3. Epub 2020 Feb 24.
Bielack SS, Cox MC, Nathrath M, Apel K, Blattmann C, Holl T, Jenewein R, Klenk U, Klothaki P, Muller-Abt P, Ortega-Lawerenz S, Reynolds M, Scheer M, Simon-Klingenstein K, Stegmaier S, Tupper R, Vokuhl C, von Kalle T. Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion. Ann Oncol. 2019 Nov 1;30(Suppl_8):viii31-viii35. doi: 10.1093/annonc/mdz382.
DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM, Nagasubramanian R, Anderson ME, Davis JL, Qamoos HE, Reynolds ME, Cruickshank S, Cox MC, Hawkins DS, Mascarenhas L, Pappo AS. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018 Nov 1;124(21):4241-4247. doi: 10.1002/cncr.31701. Epub 2018 Sep 11.
Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, Nagasubramanian R, Davis JL, Rudzinski E, Feraco AM, Tuch BB, Ebata KT, Reynolds M, Smith S, Cruickshank S, Cox MC, Pappo AS, Hawkins DS. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018 May;19(5):705-714. doi: 10.1016/S1470-2045(18)30119-0. Epub 2018 Mar 29.
Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018 Feb 22;378(8):731-739. doi: 10.1056/NEJMoa1714448.
Primary Completion
July 20, 2024
Actual (reported)Study Completion
September 30, 2026
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
Last Updated
June 22, 2025
Record last verified: 2025-06
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